Refractories, fibers, aluminosilicate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From: 24th May 1988 To: 14th November 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

There was little attempt to justify the use of the doses particularly the MTD. The gravimetric estimate of 30 mg/m3 was used for all types of fibre in two species with no further range finding efforts. Otherwise the study was a very high quality but the test substance used was heavily contaminated by non fibrous particulate not produced during the normal handling and use of this product. These particles were not completely enumerated during the study and their significance not realised.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Reference 2

Reference Type:

publication

Title:

The Importance of fibre biopersistence and lung Dose in Determining the chronic Inhalation -Effects of X607,RCF1 and Chryotile Asbestos in rats

Author:

Hesterberg TW et al.

Year:

1998

Bibliographic source:

Toxicology and Applied Phamacology 153, 68-82

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

to make it suitable for use with fibres

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

oxo[(oxoalumanyl)oxy]alumane; silanedione

EC Number:

604-314-4

Cas Number:

142844-00-6

Molecular formula:

amorphous glass Si(n)O(3n+1) polymeric anions bonded to Zr and Al(3+)

IUPAC Name:

oxo[(oxoalumanyl)oxy]alumane; silanedione

Details on test material:

- Name of test material (as cited in study report): RCF 1
- Substance type: mineral fibre
- Physical state: solid
- Analytical purity: assumed>99%
- Stability under test conditions:indefinite
- Batch number : 7309
- Storage condition of test material:room temperature , protected from the light

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, Stone Ridge, N.Y., USA
- Age at study initiation: 8 weeks
- Weight at study initiation: 130-150g
- Housing: during exposure and beginning of recovered, stainless steel wire cages, during major part of recovery period Macrolon Cages Type IV with standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Kliba 343, rat/mouse maintenance diet
- Water: ad libitum
- Acclimation period: 18 days from day of delivery

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12hrs

IN-LIFE DATES: From: 24th May 1988 To: 14th November 1990

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Fibre sizes are not reported as MMAD. Fibre respirability is determined by fibre diameters with mass playing a secondary role. The aerosol:WHO fibres had a mean length of 16+- 3 and a diameter of 0.8+- 0.2.

Details on inhalation exposure:

Exposure was for 104 weeks. The aerosol was generated by a brush disperser, fed with test material. Static was neutralised using a 63 nickel radiation source. The airflow to each animal was 1 litre/min calculated to be laminar. The animals were restrained in Battelle tubes.

-GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: flow -past nose-only design
- Method of holding animals in test chamber: makrolon tubes, batelle?
- System of generating particulates/aerosols: fibres were aerosolised using a stepping motor and stainless steel brush to bring them into the tangential air stream, following aerosolisation the fibres passed through a Nickel63 charge neutraliser to reduce electrostatic charge
- Temperature, humidity, pressure in air chamber: 22degC, 30-70%
- Air flow rate: 0.9 litre/ airport/min?
- Method of particle size determination: fibre size measurements carried out by SEM

TEST ATMOSPHERE
- Brief description of analytical method used: mass concentration (gravimetric), fibre number concentration, fibre size measurements and impactor sampling.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Fibres were collected on membrane filters and quanitified by weighing and microscopy. Fibre lengths were measured using light microscopy and diameters using SEM.

Duration of treatment / exposure:

104 weeks followed by 23 weeks recovery (until survival less than 20%)

Frequency of treatment:

6 hours/day/5days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
RCF1 - 162 WHO f/ml +/- 37
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
RCF1 - 91 WHO f/ml +/- 34
Basis:
analytical conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
RCF1 - 36 WHO f/ml +/-17
Basis:
analytical conc.

No. of animals per sex per dose:

140 males

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:as fractions of the dose used in the study report number 092507 (30mg) section 7.7.2
- Rationale for animal assignment (if not random):random

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily prior and following exposure and once daily on non- exposure days

BODY WEIGHT: Yes
- Time schedule for examinations:each during acclimation period , weekly dueing the first 13 weeks and at least monthly thereafter

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Samples of neoplastic tissue were taken and sent frozen in liquid nitrogen to CIIT North Carolina. Lungs were examined under a dissection microscope for detection and identification of small macroscopic lesions. Lungs were inflated with formaldehyde photographed and sections taken for histopathology after sacrifices at 13, 26, 39 and 52 weeks lungs were instilled with Karnowski's fixative and sampled as detailed in full study report.

Statistics:

Body weight and organ weight were analysed using Dunnetts' test ,age specific survival rates were calculated . Statistical evaluations for the neoplastic lesions was performed according to Peto et al 1980.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Other effects:

not specified

Details on results:

The exposures and tumour and fibrosis data are shown in table 1

Effect levels

Key result

Dose descriptor:

LOAEC

Remarks:

Fibrosis

Effect level:

ca. 9 - < 16 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

Fibrosis at 16 and 9 mg/m3 just reached significant levels but not at the 3 mg/m3. None of the tumour incidences were higher than the the historical control values for this strain of animals

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1 Exposure conditions and results for the 3 exposure levels of RCF and control (air).

Number of animals at risk	Aerosol conc. f/ml (SD) Mg/m3 (SD)	Concentration of Non-fibrous particles <3µm diameter (mean no. of particles/ml)	Aerosol fibre dimensions   Geometric mean (GSD		Fibrosis   (Wagner Grade)	Tumour Incidence %
			diameter	length		Lung	Mesothelial
132	na	na	na	na	1	0.8	0
126	162 (37) 16.5 (1.1)	156	0.82 (1.99)	13.8 (2.4)	4.2	1.6	0
128	91 (34)  8.8 (0.7)	141	0.80 (2.03)	13.9 (2.5)	4.0	3.9	0.8
125	36 (17) 3.0 (0.4)	51	0.80 (2.06)	13.5(2.6)	3.2	1.6	0

Applicant's summary and conclusion

Conclusions:

The particle contaminated RCF1 was still capable of causing overload at these low concentrations used but not until late in life consequently there was not a significant increase in tumour burden.

Executive summary:

The deficencies in the 30mg/m3 study (section 7.5.3.5) were repeated in this lower dose study. Only one of the four samples of RCF was tested at these concentrations